Journal
JOURNAL OF IMMUNOLOGY
Volume 197, Issue 7, Pages 2673-2685Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600854
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Funding
- BBSRC [BBS/E/B/0000H322, BB/J00152X/1, BBS/E/B/000C0407] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J00152X/1, BBS/E/B/0000M983, BBS/E/B/000C0407] Funding Source: Medline
- Medical Research Council Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000M983, BB/J00152X/1, 976494, BBS/E/B/0000H322, BBS/E/B/000C0407] Funding Source: researchfish
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The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly to enforce the beta-selection checkpoint during thymopoiesis, yet their molecular targets remain largely unknown. In this study, we identify these targets on a genome-wide scale in primary mouse thymocytes and show that Zfp36l1/l2 regulate DNA damage response and cell cycle transcripts to ensure proper beta-selection. Double-negative 3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with postselected double-negative 3b cells despite the absence of intracellular TCR beta and reduced IL-7 signaling. Our findings show that in addition to controlling the timing of proliferation at beta-selection, posttranscriptional control by Zfp36l1/l2 limits DNA damage responses, which are known to promote thymocyte differentiation. Zfp36l1/l2 therefore act as posttranscriptional safeguards against chromosomal instability and replication stress by integrating pre-TCR and IL-7 signaling with DNA damage and cell cycle control.
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